Gene therapy for prostate cancer using the cytosine deaminase/uracil phosphoribosyttransferase suicide system

Background Cytosine deaminase (CD) activates prodrug 5-FC to 5-FU and is used for suicide gene therapy (the CD/5-FC system). E. coli uracil phosphoribosyltransferase (UPRT) is a pyrimidine salvage enzyme that directly converts 5-FU into 5-fluorouridine monophosphate and improves the antitumoral effect of 5-FU. This study demonstrates the effectiveness of transduction of the UPRT gene in addition to CD/5-FC cancer suicide gene therapy. Methods We investigated a combined suicide gene transduction therapy for human hormone independent prostate cancer cell line DU145 using two separate adenovirus vectors expressing the E. coli CD and E coli UPRT genes and systemic 5-FC administration (the CD+UPRT/5-FC system). Results Cells transfected with AdCA-UPRT showed approximately 57 times lower IC50 to 5-FU compared with those transfected with AdCA-LacZ. Furthermore, cells transfected with AdCA-CD and AdCA-UPRT proved to be more sensitive to 5-FC compared with those transfected with AdCA-CD. Intratumoral injection of AdCA-CD and AdCA-UPRT drastically suppressed the growth of tumors which had generated from DU145 cells inoculated into athymic (nude) mice compared with those injected with AdCA-LacZ or AdCA-LacZ and AdCA-CD. Conclusions These results suggest that the CD+UPRT/5-FC system could be a powerful factor in human prostate cancer suicide gene therapy. Copyright (C) 2002 John Wiley Sons, Ltd.